100 years of glucagon and 100 more Wewer Albrechtsen, Nicolai J.; Holst, Jens J.; Cherrington, Alan D. ...
Diabetologia,
08/2023, Letnik:
66, Številka:
8
Journal Article
Recenzirano
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The peptide hormone glucagon, discovered in late 1922, is secreted from pancreatic alpha cells and is an essential regulator of metabolic homeostasis. This review summarises experiences since the ...discovery of glucagon regarding basic and clinical aspects of this hormone and speculations on the future directions for glucagon biology and glucagon-based therapies. The review was based on the international glucagon conference, entitled ‘A hundred years with glucagon and a hundred more’, held in Copenhagen, Denmark, in November 2022. The scientific and therapeutic focus of glucagon biology has mainly been related to its role in diabetes. In type 1 diabetes, the glucose-raising properties of glucagon have been leveraged to therapeutically restore hypoglycaemia. The hyperglucagonaemia evident in type 2 diabetes has been proposed to contribute to hyperglycaemia, raising questions regarding underlying mechanism and the importance of this in the pathogenesis of diabetes. Mimicry experiments of glucagon signalling have fuelled the development of several pharmacological compounds including glucagon receptor (GCGR) antagonists, GCGR agonists and, more recently, dual and triple receptor agonists combining glucagon and incretin hormone receptor agonism. From these studies and from earlier observations in extreme cases of either glucagon deficiency or excess secretion, the physiological role of glucagon has expanded to also involve hepatic protein and lipid metabolism. The interplay between the pancreas and the liver, known as the liver–alpha cell axis, reflects the importance of glucagon for glucose, amino acid and lipid metabolism. In individuals with diabetes and fatty liver diseases, glucagon’s hepatic actions may be partly impaired resulting in elevated levels of glucagonotropic amino acids, dyslipidaemia and hyperglucagonaemia, reflecting a new, so far largely unexplored pathophysiological phenomenon termed ‘glucagon resistance’. Importantly, the hyperglucagonaemia as part of glucagon resistance may result in increased hepatic glucose production and hyperglycaemia. Emerging glucagon-based therapies show a beneficial impact on weight loss and fatty liver diseases and this has sparked a renewed interest in glucagon biology to enable further pharmacological pursuits.
Graphical Abstract
People with obesity and type 2 diabetes have a high prevalence of metabolic-associated steatotic liver disease, hyperlipidemia and cardiovascular disease. Glucagon increases hepatic glucose ...production; it also decreases hepatic fat accumulation, improves lipidemia and increases energy expenditure. Pharmaceutical strategies to antagonize the glucagon receptor improve glycemic outcomes in people with diabetes and obesity, but they increase hepatic steatosis and worsen dyslipidemia. Co-agonism of the glucagon and glucagon-like peptide-1 (GLP-1) receptors has emerged as a promising strategy to improve glycemia in people with diabetes and obesity. Addition of glucagon receptor agonism enhances weight loss, reduces liver fat and ameliorates dyslipidemia. Prior to clinical use, however, further studies are needed to investigate the safety and efficacy of glucagon and GLP-1 receptor co-agonists in people with diabetes and obesity and related conditions, with specific concerns regarding a higher prevalence of gastrointestinal side effects, loss of muscle mass and increases in heart rate. Furthermore, co-agonists with differing ratios of glucagon:GLP-1 receptor activity vary in their clinical effect; the optimum balance is yet to be identified.
•Glucagon antagonists worsen hepatic steatosis and hyperlipidemia in people with diabetes and obesity.•Glucagon/GLP-1 receptor co-agonism improves weight loss, hepatic steatosis and hyperlipidemia, without worsening glycemia.•Glucagon/GLP-1 receptor co-agonists have a high rate of gastrointestinal adverse effects.
With obesity rates growing globally, there is a paramount need for new obesity pharmacotherapies to tackle this pandemic.
This review focuses on the design of therapeutics that target the ...glucose-dependent insulinotropic polypeptide receptor (GIPR) to aid weight loss. The authors highlight the paradoxical observation that both GIPR agonism and antagonism appear to provide metabolic benefits when combined with glucagon-like peptide-1 receptor (GLP-1 R) agonism. The therapeutic potential of compounds that target the GIPR alongside the GLP-1 R and the glucagon receptor are discussed, and the impressive clinical findings of such compounds are reviewed.
In this area, the translation of pre-clinical findings to clinical studies appears to be particularly difficult. Well-designed physiological studies in man are required to answer the paradox highlighted above, and to support the safe future development of a combination of GLP-1 R/GIPR targeting therapies.
Obesity represents an important public health challenge for the twenty-first century: globalised, highly prevalent and increasingly common with time, this condition is likely to reverse some of the ...hard-won gains in mortality accomplished in previous centuries. In the search for safe and effective therapies for obesity and its companion, type 2 diabetes mellitus (T2D), the gut hormone glucagon-like peptide-1 (GLP-1) has emerged as a forerunner and analogues thereof are now widely used in treatment of obesity and T2D, bringing proven benefits in improving glycaemia and weight loss and, notably, cardiovascular outcomes. However, GLP-1 alone is subject to limitations in terms of efficacy, and as a result, investigators are evaluating other gut hormones such as glucose-dependent insulinotropic peptide (GIP), glucagon and peptide YY (PYY) as possible partner hormones that may complement and enhance GLP-1’s therapeutic effects. Such combination gut hormone therapies are in pharmaceutical development at present and are likely to make it to market within the next few years. This review examines the physiological basis for combination gut hormone therapy and presents the latest clinical results that underpin the excitement around these treatments. We also pose, however, some hard questions for the field which need to be answered before the full benefit of such treatments can be realised.
Obesity and Type 2 diabetes represent global health challenges, and there is an unmet need for long-lasting and effective pharmacotherapies. Although long-acting glucagon-like peptide-1 (GLP-1) ...analogues are now in routine use for diabetes and are now being utilised for obesity
, the need for ever better treatments has driven the development of co-agonists, with the theoretical advantages of improved efficacy by targeting multiple pathways and reduced adverse effects. In this review, we highlight the past and present progress in our understanding and development of treatments based on GLP-1/glucagon co-agonism. We also reflect on the divergent effects of varying the GLP-1:glucagon activity and ratio in the context of pre-clinical and human clinical trial findings. In particular, the multiple metabolic actions of glucagon highlight the importance of understanding the contributions of individual hormone action to inform the safe, effective and tailored use of GLP-1/glucagon co-agonists to target weight loss and metabolic disease in the future.
Aims
To determine whether a continuous infusion of a glucagon‐like peptide receptor (GLP‐1R)/glucagon receptor (GCGR) co‐agonist, G3215 is safe and well tolerated in adults with overweight or ...obesity.
Methods
A phase 1 randomized, double blind, placebo‐controlled trial of G3215 in overweight or obese participants, with or without type 2 diabetes.
Results
Twenty‐six participants were recruited and randomized with 23 completing a 14‐day subcutaneous infusion of G3215 or placebo. The most common adverse events were nausea or vomiting, which were mild in most cases and mitigated by real‐time adjustment of drug infusion. There were no cardiovascular concerns with G3215 infusion. The pharmacokinetic characteristics were in keeping with a continuous infusion over 14 days. A least‐squares mean body weight loss of 2.39 kg was achieved with a 14‐day infusion of G3215, compared with 0.84 kg with placebo infusion (p < .05). A reduction in food consumption was also observed in participants receiving G3215 and there was no deterioration in glycaemia. An improved lipid profile was seen in G3215‐treated participants and consistent with GCGR activation, a broad reduction in circulating amino acids was seen during the infusion period.
Conclusion
An adaptive continuous infusion of the GLP‐1/GCGR co‐agonist, G3215, is safe and well tolerated offering a unique strategy to control drug exposure. By allowing rapid, response‐directed titration, this strategy may allow for mitigation of adverse effects and afford significant weight loss within shorter time horizons than is presently possible with weekly GLP‐1R and multi‐agonists. These results support ongoing development of G3215 for the treatment of obesity and metabolic disease.
Background and Aims
Sleeve gastrectomy (VSG) leads to improvement in hepatic steatosis, associated with weight loss. The aims of this study were to investigate whether VSG leads to weight‐loss ...independent improvements in liver steatosis in mice with diet‐induced obesity (DIO); and to metabolically and transcriptomically profile hepatic changes in mice undergoing VSG.
Methods
Mice with DIO were treated with VSG, sham surgery with subsequent food restriction to weight‐match to the VSG group (Sham‐WM), or sham surgery with return to unrestricted diet (Sham‐Ad lib). Hepatic steatosis, glucose tolerance, insulin and glucagon resistance, and hepatic transcriptomics were investigated at the end of the study period and treatment groups were compared with mice undergoing sham surgery only (Sham‐Ad lib).
Results
VSG led to much greater improvement in liver steatosis than Sham‐WM (liver triglyceride mg/mg 2.5 ± 0.1, 2.1 ± 0.2, 1.6 ± 0.1 for Sham‐AL, Sham‐WM and VSG respectively; p = 0.003). Homeostatic model assessment of insulin resistance was improved following VSG only (51.2 ± 8.8, 36.3 ± 5.3, 22.3 ± 6.1 for Sham‐AL, Sham‐WM and VSG respectively; p = 0.03). The glucagon‐alanine index, a measure of glucagon resistance, fell with VSG but was significantly increased in Sham‐WM (9.8 ± 1.7, 25.8 ± 4.6 and 5.2 ± 1.2 in Sham Ad‐lib, Sham‐WM and VSG respectively; p = 0.0003). Genes downstream of glucagon receptor signalling which govern fatty acid synthesis (Acaca, Acacb, Me1, Acly, Fasn and Elovl6) were downregulated following VSG but upregulated in Sham‐WM.
Conclusions
Changes in glucagon sensitivity may contribute to weight‐loss independent improvements in hepatic steatosis following VSG.
Objectives
Peptide tyrosine tyrosine (PYY) exists as two species, PYY1‐36 and PYY3‐36, with distinct effects on insulin secretion and appetite regulation. The detailed effects of bariatric surgery on ...PYY1‐36 and PYY3‐36 secretion are not known as previous studies have used nonspecific immunoassays to measure total PYY. Our objective was to characterize the effect of sleeve gastrectomy (SG) and Roux‐en‐Y gastric bypass (RYGB) on fasting and postprandial PYY1‐36 and PYY3‐36 secretion using a newly developed liquid chromatography‐tandem mass spectrometry (LC‐MS/MS) assay.
Design and Subjects
Observational study in 10 healthy nonobese volunteers and 30 participants with obesity who underwent RYGB (n = 24) or SG (n = 6) at the Imperial Weight Centre NCT01945840. Participants were studied using a standardized mixed meal test (MMT) before and 1 year after surgery. The outcome measures were PYY1‐36 and PYY3‐36 concentrations.
Results
Presurgery, the fasting and postprandial levels of PYY1‐36 and PYY3‐36 were low, with minimal responses to the MMT, and these did not differ from healthy nonobese volunteers. The postprandial secretion of both PYY1‐36 and PYY3‐36 at 1 year was amplified after RYGB, but not SG, with the response being significantly higher in RYGB compared with SG.
Conclusions
There appears to be no difference in PYY secretion between nonobese and obese volunteers at baseline. At 1 year after surgery, RYGB, but not SG, is associated with increased postprandial secretion of PYY1‐36 and PYY3‐36, which may account for long‐term differences in efficacy and adverse effects between the two types of surgery.
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